Genetic control of thymic NKT cell number

自身免疫性疾病是由多个基因和环境因素之间的复杂相互作用引起的。由于这种复杂性，鉴定相关基因的尝试在很大程度上都没有成功。该项目选择关注导致1型（自身免疫性）糖尿病的基因的特定子集-控制一小群调节性白色血细胞（称为NKT细胞）的子集。申请人先前已经表明，易患糖尿病的小鼠品系（NOD小鼠品系）缺乏NKT细胞，并且如果通过输血来替代它们，则小鼠免受疾病的影响。在选择性育种实验中，他们已经能够证明NKT细胞数量的缺乏是遗传性的，并且已经定位了这些基因的染色体位置。此外，他们还培育出了特殊的NOD小鼠品系，这些小鼠具有这些基因的正常拷贝和增加的NKT细胞数量。该项目旨在确定负责控制NKT细胞数量的遗传编码序列。它将综合利用基因绘图、特定育种、基因分析和转基因生物的生产。这项研究的结果将是确定至少一个控制NKT细胞数量的基因。然后将在患者中研究这些基因，以确定它是否在人类疾病中发挥作用。

Autoimmune diseases result from a complex interaction between multiple genes and environmental factors. Attempts to identify the genes involved have been largely unsuccessful because of this complexity. This project has chosen to focus on a particular subset of the genes that cause type 1 (autoimmune) diabetes - the subset that control a small population of regulatory white blood cells, termed NKT cells. The applicants have previously shown that a mouse strain prone to diabetes, the NOD mouse strain, is deficient in NKT cells and if they are replaced by transfusion, the mice are protected from disease. In selective breeding experiments, they have been able to show that the deficiency in NKT cell numbers is genetic, and have localised the chromosomal positions of these genes. Furthermore, they have produced specially bred lines of NOD mice that have normal copies of these genes and increased numbers of NKT cells. This project aims to identify the genetic coding sequences responsible for controlling numbers of NKT cells. It will use a combination of genetic mapping, specific breeding, gene analyses and the production of genetically modified organisms. The result of this study will be the identification of at least one of the genes that control NKT cell numbers. These gene(s) will then be studied in patients to determine if it plays a role in human disease.